Pharmaceutical formulations

Abstract

Improved pharmaceutical compositions are provided comprising one or more solubilized HIV protease inhibiting compounds having improved solubility properties in a medium and/or long chain fatty acid, or mixtures thereof, a pharmaceutically acceptable alcohol, and water.

1. A pharmaceutical composition comprising a solution which comprises:
 (a) (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)-methyl)amino)carbonyl)-L-valinyl)amino)-2-(N-((5thiazolyl)methoxy-carbonyl)-amino)-1,6-diphenyl-3-hydroxyhexane (ritonavir) or a combination of ritonavir and another HIV protease inhibiting compound, or pharmaceutically acceptable salts thereof, in an amount of from 1% to 50% by weight of said solution; 
 (b) a pharmaceutically acceptable medium and/or long chain fatty acid, or a mixture of pharmaceutically acceptable medium and/or long chain fatty acids, in an amount of from 30% to 75% by weight of said solution; 
 (c) ethanol or propylene glycol in an amount of from 1% to 15% by weight of said solution; 
 (d) water in an amount of from 0.4% to 3.5% by weight of said solution; and, optionally, 
 (e) a pharmaceutically acceptable surfactant. 
 
     
     
       2. The composition according to  claim 1 , wherein said solution comprises ritonavir and said another HIV protease inhibiting compound. 
     
     
       3. The composition according to  claim 2 , wherein said another HIV protease inhibiting compound is (2S,3 S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane (ABT-378). 
     
     
       4. The composition according to  claim 2 , wherein said another HIV protease inhibiting compound is a compound selected from the group consisting of: 
       (1) (2S,3S,5 S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methyl-butanoyl)amino-1,6-diphenylhexane, 
       (2) N-(2(R)-hydroxy-1 (S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamide (indinavir), 
       (3) N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3 (S)-carboxamide (saquinavir), 
       (4) 5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide, 
       (5) 1-Naphthoxyacetyl-beta-methylthio-Ala-(2S, 3S)-3-amino-2-hydroxy-4-butanoyl 1,3-thiazolidine-4-t-butylamide, 
       (6) 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3 S)-3-amino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-butylamide, 
       (7) [1S-[1R-(R-),2S*])—N 1  [3-[[[(1,1-dimethylethyl)amino]carbonyl](2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide,
 (8) 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       5. The composition according to  claim 1 , wherein said surfactant is in an amount of from 2% to 20% by weight of said solution. 
     
     
       6. The composition according to  claim 1 , wherein said solution comprises ritonavir or a combination of ritonavir and said another HIV protease inhibiting compound, or pharmaceutically acceptable salts thereof, in an amount of from 10 to 40% by weight of said solution. 
     
     
       7. The composition according to  claim 1 , wherein said solution comprises a pharmaceutically acceptable organic solvent in an amount of from 50% to 75% by weight of said solution, and said solvent includes:
 (a) a pharmaceutically acceptable medium and/or long chain fatty acid, or a mixture of pharmaceutically acceptable medium and/or long chain fatty acids, in an amount of from 30% to 75% by weight of said solution; and 
 (c) ethanol or propylene glycol in an amount of from 1% to 15% by weight of said solution. 
 
     
     
       8. The composition of  claim 1 , wherein said solution comprises water in an amount of from 0.4% to 1.5% by weight of said solution. 
     
     
       9. The composition according to  claim 1 , wherein said solution comprises oleic acid in an amount of from 30% to 75% by weight of said solution. 
     
     
       10. The composition according to  claim 1 , wherein said surfactant is polyoxyl 35 castor oil. 
     
     
       11. The composition according to  claim 1 , wherein said solution comprises:
 (a) ritonavir in an amount from 1% to 30% by weight of said solution; 
 (b) a pharmaceutically acceptable medium and/or long chain fatty acid in an amount of from 30% to 75% by weight of said solution; 
 (c) ethanol in an amount of from 1% to 15% by weight of said solution; 
 (d) water in an amount of from 0.4% to 3.5% by weight of said solution; and 
 (e) polyoxyl 35 castor oil in an amount of from 0% to 20% by weight of said solution. 
 
     
     
       12. The composition of  claim 1 , wherein said solution comprises:
 (a) a combination of ritonavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl]-amino-1,6-diphenylhexane, in an amount of from 1% to 45% by weight of said solution; 
 (b) a pharmaceutically acceptable medium and/or long chain fatty acid in an amount of from 30% to 75% by weight of said solution; 
 (c) propylene glycol in an amount of from 1% to 15% by weight of said solution; 
 (d) water in an amount of from 0.4% to 3.5% by weight of said solution; and 
 (e) polyoxyl 35 castor oil in an amount of from 0% to 20% by weight of said solution. 
 
     
     
       13. The composition according to  claim 1 , wherein said solution comprises:
 (a) ritonavir in an amount from 1% to 30% by weight of said solution; 
 (b) oleic acid in an amount of from 30% to 75% by weight of said solution; 
 (c) ethanol in an amount of from 1% to 15% by weight of said solution; 
 (d) water in an amount of from 0.4% to 3.5% by weight of said solution; and 
 (e) polyoxyl 35 castor oil in an amount of from 0% to 20% by weight of said solution. 
 
     
     
       14. The composition according to  claim 13 , wherein said solution comprises:
 (a) ethanol in an amount of from 3% to 12% by weight of said solution; and 
 (b) polyoxyl 35 castor oil in an amount of from 2.5% to 10% by weight of said solution. 
 
     
     
       15. The composition of  claim 1 , wherein said solution comprises:
 (a) ritonavir in an amount of 10% by weight of said solution; 
 (b) oleic acid in an amount of from 70% to 75% by weight of said solution; 
 (c) ethanol in an amount of from 3% to 12% by weight of said solution; 
 (d) water in an amount of from 0.4% to 1.5% by weight of said solution; and 
 (e) polyoxyl 35 castor oil in an amount of 6% by weight of said solution. 
 
     
     
       16. The composition of  claim 1 , wherein said solution comprises:
 (a) a combination of ritonavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl]-amino-1,6-diphenylhexane, in an amount of from 1% to 45% by weight of said solution; 
 (b) oleic acid in an amount of from 30% to 75% by weight of said solution; 
 (c) propylene glycol in an amount of from 1% to 8% by weight of said solution; 
 (d) water in an amount of from 0.4% to 3.5% by weight of said solution; and 
 (e) polyoxyl 35 castor oil in an amount of from 0% to 20% by weight of said solution. 
 
     
     
       17. The composition of  claim 1 , wherein said solution comprises:
 (a) a combination of ritonavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl]-amino-1,6-diphenylhexane, in an amount of 10% by weight of said solution; 
 (b) oleic acid in an amount of from 70% to 75% by weight of said solution; 
 (c) propylene glycol in an amount of from 1% to 15% by weight of said solution; 
 (d) water in an amount of from 0.4% to 1.5% by weight of said solution; and 
 (e) polyoxyl 35 castor oil in an amount of 6% by weight of said solution. 
 
     
     
       18. The composition according to  claim 1 , further comprising a hard or soft elastic gelatin capsule which encapsulates said solution. 
     
     
       19. The composition according to  claim 3 , further comprising a hard or soft elastic gelatin capsule which encapsulates said solution. 
     
     
       20. The composition according to  claim 9 , further comprising a hard or soft elastic gelatin capsule which encapsulates said solution. 
     
     
       21. The composition according to  claim 11 , further comprising a hard or soft elastic gelatin capsule which encapsulates said solution. 
     
     
       22. The composition according to  claim 12 , further comprising a hard or soft elastic gelatin capsule which encapsulates said solution. 
     
     
       23. The composition according to  claim 13 , further comprising a hard or soft elastic gelatin capsule which encapsulates said solution. 
     
     
       24. The composition according to  claim 15 , further comprising a hard or soft elastic gelatin capsule which encapsulates said solution. 
     
     
       25. The composition according to  claim 16 , further comprising a hard or soft elastic gelatin capsule which encapsulates said solution. 
     
     
       26. The composition according to  claim 17 , further comprising a hard or soft elastic gelatin capsule which encapsulates said solution.